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This thesis presents the design, implementation and partial experimental characterization of a multi-modality scanning-contact microscope (SCM) with application in biomedical imaging. Bench-top light microscopes are bulky and expensive and provide only one imaging modality. The resolution of most conventional lens-less (contact) microscopes is limited by their pixel size which renders them unsuitable for applications demanding high resolution such as cell imaging. The SCM's imaging component is a custom-made CMOS imager in the AMS0.35m imaging process. Six pixel types are integrated into the imager, which enable the SCM to support six imaging modalities. For sub-pixel resolution imaging, a specialized pixel layout is used which allows the system to support a super-resolution algorithm which takes multiple images with sub-pixel shifts as its input and generates a single high-resolution image. Each pixel type may generate an output voltage or current, depending on whether it is active or passive. A low-power dual-input 2nd order ADC with an SNR of 78dB is implemented to accommodate both current and voltage inputs while preserving noise-shaping characteristics for both inputs.
This book covers important aspects of modern optical microscopy and image restoration technologies. Instead of pure optical treatment, the book is delivered with the consideration of the scientists who utilize optical microscopy in their daily research. However, enough details are provided in basic imaging principles, optics and instrumentation in microscopy, spherical aberrations, deconvolution and image restoration. A number of microscopic technologies such as polarization, confocal and multi-photon microscopy are highlighted with their applications in biological and materials sciences/engineering.
The work covers a multimodal microscope technology for the analysis, manipulation and transfer of materials and objects in the submicrometer range. An atomic force microscope (AFM) allows imaging of the surface topography and a Scanning Microwave Microscope (SMM) detects electromagnetic properties, both operating in a Scanning Electron Microscope (SEM). The described technology demonstrator allows to observe the region-of-interest live with the SEM, while at the same time a characterization with interacting evanescent near-field microwaves and intermolecular forces takes place. engl.
A thorough examination of lab-on-a-chip circuit-level operations to improve system performance A rapidly aging population demands rapid, cost-effective, flexible, personalized diagnostics. Existing systems tend to fall short in one or more capacities, making the development of alternatives a priority. CMOS Integrated Lab-on-a-Chip System for Personalized Biomedical Diagnosis provides insight toward the solution, with a comprehensive, multidisciplinary reference to the next wave of personalized medicine technology. A standard complementary metal oxide semiconductor (CMOS) fabrication technology allows mass-production of large-array, miniaturized CMOS-integrated sensors from multi-modal domains with smart on-chip processing capability. This book provides an in-depth examination of the design and mechanics considerations that make this technology a promising platform for microfluidics, micro-electro-mechanical systems, electronics, and electromagnetics. From CMOS fundamentals to end-user applications, all aspects of CMOS sensors are covered, with frequent diagrams and illustrations that clarify complex structures and processes. Detailed yet concise, and designed to help students and engineers develop smaller, cheaper, smarter lab-on-a-chip systems, this invaluable reference: Provides clarity and insight on the design of lab-on-a-chip personalized biomedical sensors and systems Features concise analyses of the integration of microfluidics and micro-electro-mechanical systems Highlights the use of compressive sensing, super-resolution, and machine learning through the use of smart SoC processing Discusses recent advances in complementary metal oxide semiconductor-integrated lab-on-a-chip systems Includes guidance on DNA sequencing and cell counting applications using dual-mode chemical/optical and energy harvesting sensors The conventional reliance on the microscope, flow cytometry, and DNA sequencing leaves diagnosticians tied to bulky, expensive equipment with a central problem of scale. Lab-on-a-chip technology eliminates these constraints while improving accuracy and flexibility, ushering in a new era of medicine. This book is an essential reference for students, researchers, and engineers working in diagnostic circuitry and microsystems.
"The objective of this thesis is to present the fabrication of a multiphoton microscope and the underlying theory responsible for its proper functioning. A basic introduction to nonlinear optics will give the necessary knowledge to the reader to understand the optical effects involved. Femtosecond laser pulses will be presented and characterized. Each part of the microscope, their integration and the design of the microscope will be discussed. The basic concepts of laser scanning microscopy are also required to explain the design of the scanning optics. Fast scanning problems and their solutions are also briefly viewed. As a working proof, the first images taken with the microscope will be presented. Fluorescent beads, rat tail tendon, gold nanoparticles and pollen grain images using various nonlinear effects will be shown and discussed." --
"The goal of this engineering thesis was to restore and upgrade a legacy electro-optical microscopy system for use in experimental research. This was accomplished through the application of a broad range of engineering disciplines and problem solving skills. The operation of the legacy system was assessed as a whole, and the performance of each component was characterized and compared to the design requirements. Malfunctioning technology was repaired, when possible, and new devices and software were implemented to enhance the capabilities of the original design. The resulting imaging system is capable of producing data on par with the legacy system and serves as a base for implementing additional microscopy techniques and future upgrades"--Author's abstract.
Serial block-face scanning electroni microscopy (SBEM) promises to revolutionize structural biology and neuroanatomical research by allowing the 3-dimensional reconstruction of relatively large regions of tissue and cell arrays at near nanometer-scale resolution. This approach employs and automated ultra-microtome fitted into a scanning electronic microscope that images the specimen surface, or block-face, following each iterative nanometer thin cut. However, a principal limitation of this approach is the resolution obtainable using backscatter electrons at low accelerating voltages due to the build up of electrostatic charges on the block-face, otherwise known as "charging." Herein, we present a specimen preparation protocol that implements heavy metal staining, and a series of methods for use of conductive materials, as either a dopant, covalent linker, or metal coordinated matrix (scaffold), in the epoxy resin. These approaches in staining and enhancing resin conductivity lead to substantial improvement in contrast and image resolution for accelerating voltages at, or below 2.0keV for SBEM. To build connections from the 3-dimensional data sets obtained by SBEM to other imaging modalities for broader context and insight, developments in region of interest (ROI) tracking across light, x-ray and electronic microscopy using upconverting nanoparticles, as fiducial markers and labels, have led to advanced efficiency in the correlated microscopy workflow. As a result, a universal fiducial/marker ties together the representing datasets for multi-modal imaging, and adds further context to the specimen's region of interest.
"Biological and biomedical research is often contingent upon microscopy techniques for observation and studying of biological features and processes, and subsequent analysis. For many applications, it is necessary that the selected imaging system provide high spatial resolution and large field-of-view, in order to be able to visualize individual biological structures or agents within the sample, while capturing an area large enough, where meaningful analysis, such as particle tracking, could be performed within a single frame. Various lens-based and lens-free imaging platforms, each with their own sets of advantages and disadvantages, offer different imaging modalities suitable for different specimens and applications, but they all suffer from a main limitation: the trade-off between spatial resolution and field-of-view. This competition cannot be eliminated but could be optimized, based on the chosen imaging system specifications. This work addresses the restrictive trade-off, and introduces a mobile phone-based illumination-imaging platform that maximizes the attainable field-of-view at high resolution, and expands the use of phone screen illumination to a lens-free platform.The thesis transitions from a broad introduction to microscopy in the biological and biomedical fields into a general protocol for identification of imaging system requirements for a targeted application, modelled after a specific example for imaging of a biocomputational microfluidic device that utilizes microorganisms as exploratory problem-solving agents. The following chapters introduce the aforementioned dual-phone system, which uses a phone camera with an external lens for imaging, to achieve a spatial resolution of at least 2 [mu]m, and a large field-of-view of 3.6 × 2.7mm. For illumination, it uses the screen of another phone to project multi-modal illumination patterns, including but not limited to bright-field, dark-field, Rheinberg illumination, point illumination, fluorescence, and differential phase contrast. Put together, this illumination-imaging system forms a novel, inexpensive, compact, portable, and versatile microscope for use in low-resource environments. It could be used in research, medical, educational, and environmental settings for both qualitative and quantitative imaging of cells, microorganisms, and other micron-sized objects. The adaptability of phone screen illumination allows it to be further integrated into lens-free imaging platforms, as well as conventional microscopes"--
We investigate a microscope design that offers high signal sensitivity and hyperspectral imaging capabilities and allows for implementation of various optical imaging approaches while its operational complexity is minimized. This system utilizes long working distance microscope objectives that enable for off-axis illumination of the tissue thereby allowing for excitation at any optical wavelength and nearly eliminating spectral noise from the optical elements. Preliminary studies using human and animal tissues demonstrate the feasibility of this approach for real-time imaging of intact tissue microstructures using autofluorescence and light scattering imaging methods.